Design, synthesis, and biological evaluation of new heterocycles bearing both silicon and phosphorus as potent MMP‐2 inhibitors

Abstract

AbstractMatrix metalloproteinases (MMPs) attracted medicinal chemists as they are biological targets that are involved in various pathophysiological processes such as extracellular matrix protein degradation, cell‐surface receptor release and cleavage, tumor growth, homeostatic control, and innate immunity. New heterocycles, bearing both silicon and phosphorus in their molecular structures, were successfully produced via reacting silylated isocyanates and/or isothiocyanates with appropriate phosphorus ylides. Reacting nucleophilic phosphacumulenes (2,6) with isocyanate 1 and isothiocyanate 9 yielded four‐membered ring heterocycles containing phosphorus and silicon (4 and 11) and six‐membered rings heterocycles (5, 8 and 12). Moreover, novel heterocycles containing two phosphorus atoms and one silicon atom were produced by the reaction of diphosphorane 13 with 1 or 9. On the other side, four‐membered (23, 26 and 29a) and six‐membered heterocyclic derivatives (20b and 29b) containing two phosphorus atoms in their structures were also obtained from the reaction of phosphallene ylide 13 and substrates (18, 21, 24 and 27). All the final compounds were tested for their MMP‐2 inhibitor activity showing IC50 values in the range of 0.0408–0.4985 μM. The thiolactam derivative 11 and the azaphosphetidin‐4‐one derivative 15, both bearing silicon and phosphorous, showed the highest activity with IC50 values of 0.0408 and 0.0693 μM, respectively, both are significantly higher than that of quercetin (IC50 = 0.1631 μM). Docking simulations were carried out for the most two active compounds 11 and 15 in the vicinity of the active site of MMP‐2 enzyme and both formed coordinate bonds with the zinc cation key interaction for MMP‐2 enzyme. In conclusion, compounds 11 and 15 can be considered as potential MMP‐2 inhibitors and can be subjected to further studies as antimetastatic agents.